Tumor, particularly malignant tumor is a disease which causes serious harm to the health of human bodies and is the second leading cause of death among all diseases in the world today. The incidence tendency of malignant tumor is rising obviously in recent years. However, the treatment effect is limited, with high metastasis rate in advanced stage and poor prognosis. Although, conventional treatments currently used in clinical such as radiotherapy, chemotherapy and surgical treatment can ease the pain to a large extent and prolong the life span, there are still many limitations of these therapies and it's difficult to improve the treatment effect further.
There are two distinct phases of tumor growth, namely from the avascular phase of slow growth to the vascular phase of rapid proliferation. Angiogenesis enables the tumors to obtain adequate nutrition and therefore complete the angiogenic switch. If there is no angiogenesis, the primary tumor will not grow to exceed 1-2 mm and tumor metastasis will not be realized. Vascular endothelial growth factor (VEGF) is a kind of growth factor which can promote endothelial cell differentiation and proliferation, promote new blood vessel formation and increase vascular permeability. It binds to vascular endothelial growth factor receptor on the surface of cells, and functions by activating tyrosine kinase signal transduction pathways. In tumor tissues, the tumor cells, invasive tumor macrophages and mast cells can secrete high levels of VEGF, stimulate the tumor vascular endothelial cells in the form of paracrine secretion, promote the proliferation and migration of endothelial cells, induce angiogenesis, promote the sustainable growth of tumor and increase vascular permeability, cause fibrin calm of the surrounding tissues, promote the invasion of monocytes, fibroblast cells and endothelial cells, facilitate the formation of tumor stroma and the entries of tumor cells into new vessels and promote tumor metastasis. Thus, the inhibition of tumor angiogenesis is considered to be one of the most promising treatments of tumors.
Bevacizumab (Avastin) is a humanized anti-human VEGF antibody (Cancer Res 1997; 57: 4593-9). It was approved as a first-line drug for the treatment of metastatic colorectal cancer by the U.S. Food and Drug Administration in 2004. However, bevacizumab is a humanized antibody that retains murine CDR regions and a few murine residues of FR regions. It is still not a fully humanized antibody and still has a problem of low affinity.